Hypertension is a complex disease process involving many pathophysiological changes. In this Program Project, the individual research topics focus on the theme that hypertension results from altered regulation of ion metabolism. The strategy of the group is to monitor many relevant variables during the development of hypertension with the goal of defining the complete sequence of events from the introduction of an intervention (experimentally imposed or genetic) to the resultant elevation in blood pressure. Among these variables are alterations in neural and endocrine factors, cellular events, and molecular and genetic characteristics. Five principal investigators form four departments (2 clinical and 2 pre-clinical) have joined to study these changes. Animal models will include genetically hypertensive rats and mineralocorticoid hypertensive rats. Clinical studies on patients with essential hypertension will be performed. Among the specific variables measured will be ion fluxes in vascular and endothelial cells, hormone levels and secretion (renin, aldosterone, catecholamine, insulin, vascular reactivity, ion channel activity, mRNA levels for specific proteins, enzyme activities (sodium-potassium ATPase), and genetic associations. From these integrated projects, a better understanding of the initiating factors of hypertension will emerge.